Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.
Jan Idkowiak, Gareth G Lavery, Vivek Dhir, Timothy G Barrett, Paul M Stewart, Nils Krone and Wiebke Arlt
Marcus Quinkler, Daniel Zehnder, Julia Lepenies, Massimiliano D Petrelli, Jasbir S Moore, Susan V Hughes, Paul Cockwell, Martin Hewison and Paul M Stewart
Objective: Renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enables selective access of aldosterone to the mineralocorticoid receptor (MR). Impaired 11β-HSD2 activity has been suggested in patients with hypertension as well as in patients with renal disease, where it may contribute to sodium retention, oedema and hypertension. To date, these studies have relied upon urinary cortisol (F) metabolite levels as surrogate markers of renal 11β-HSD2 activity.
Methods: We have directly analysed renal 11β-HSD2 mRNA expression in 95 patients undergoing kidney biopsy using TaqMan real-time PCR. Serum and 24-h urine samples were used to document underlying renal function and endocrine parameters. Urinary F and cortisone (E) metabolites were analysed using gas chromatography/mass spectrometry.
Results: Expression of 11β-HSD2 did not correlate with blood pressure or urinary Na/K ratio, but a significant positive correlation with creatinine clearance was observed (r = 0.284; P < 0.01). Immunofluorescence and confocal laser microscopy confirmed decreased 11β-HSD2 expression in patients with impaired renal function. For the first time, we showed that 11β-HSD2 mRNA expression correlated negatively with the urinary free (UF) F/E (UFF/UFE) ratio (r = 0.276; P < 0.05) as well as with the urinary tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ((THF + αTHF)/THE) ratio (r = 0.256; P < 0.05). No difference in 11β-HSD2 mRNA expression or in the UFF/UFE ratio was found between groups with no proteinuria, microalbuminuria, moderate or severe proteinuria. In contrast, the urinary (THF + αTHF)/THE ratio increased significantly (P < 0.05) in patients with severe albuminuria, suggesting increased hepatic 11β-HSD1 in those patients.
Conclusions: These data suggest that renal 11β-HSD2 expression may be represented only marginally better, if at all, by the UFF/UFE than by the (THF + αTHF)/THE ratio. Reduced renal 11β-HSD2 expression may lead to occupancy of the MR by glucocorticoids such as cortisol and may contribute to the increased sodium retention seen in patients with impaired renal function.
Rachel K Crowley, Beverly Hughes, Joanna Gray, Theresa McCarthy, Susan Hughes, Cedric H L Shackleton, Nicola Crabtree, Peter Nightingale, Paul M Stewart and Jeremy W Tomlinson
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease.
This was a prospective longitudinal observation study conducted over 5 years.
A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community.
Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.
Susanna Wiegand, Anna Richardt, Thomas Remer, Stefan A Wudy, Jeremy W Tomlinson, Beverly Hughes, Annette Grüters, Paul M Stewart, Christian J Strasburger and Marcus Quinkler
Objective: The incidence of childhood obesity and type 2 diabetes has reached epidemic proportions. Glucocorticoid excess causes central obesity and diabetes mellitus as seen in Cushing’s syndrome. The 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) regenerates active cortisol from inactive cortisone. Altered 11β-HSD1 may cause tissue-specific Cushing’s syndrome with central obesity and impaired glucose homeostasis.
Design, patients, and methods: Clinical and laboratory characteristics, and anthropometric measurements were determined in 15 male and 6 female obese pubertal children (aged 12–18 years, Tanner stages 2–5). In addition, analyses of 24-h excretion rates of glucocorticoids were also performed in 21 age-, sex-, and pubertal stage-matched non-obese children using gas chromatographic–mass spectrometric (GC–MS) analysis.
Results: 11β-HSD1 activity (urinary tetrahydrocortisol (THF) + 5α-THF/tetrahydrocortisone (THE) ratio) was lower in obese when compared with non-obese boys. In addition, obese children had a higher total cortisol metabolite excretion than non-obese children. 11β-HSD1 activity was significantly related to age in lean and obese children. Standard deviation score (SDS)-body mass index did not correlate with 11β-HSD1 activity, or with total cortisol metabolite excretion within each group. In obese children, 11β-HSD1 activity and total cortisol metabolite excretion showed no correlation to waist-to-hip ratio, fat mass (percentage of body mass), or the homeostasis model assessment of insulin resistance index.
Conclusions: In conclusion, our findings strongly suggest that 11β-HSD1 activity increases with age, and is reduced in obese boys. In addition, obese children have a higher total cortisol metabolites excretion suggesting a stimulated hypothalamus–pituitary–adrenal axis.
Mark Sherlock, Lucy Ann Behan, Mark J Hannon, Aurora Aragon Alonso, Christopher J Thompson, Robert D Murray, Nicola Crabtree, Beverly A Hughes, Wiebke Arlt, Amar Agha, Andrew A Toogood and Paul M Stewart
Patients with hypopituitarism have increased morbidity and mortality. There is ongoing debate about the optimum glucocorticoid (GC) replacement therapy.
To assess the effect of GC replacement in hypopituitarism on corticosteroid metabolism and its impact on body composition.
Design and patients
We assessed the urinary corticosteroid metabolite profile (using gas chromatography/mass spectrometry) and body composition (clinical parameters and full body DXA) of 53 patients (19 female, median age 46 years) with hypopituitarism (33 ACTH-deficient/20 ACTH-replete) (study A). The corticosteroid metabolite profile of ten patients with ACTH deficiency was then assessed prospectively in a cross over study using three hydrocortisone (HC) dosing regimens (20/10 mg, 10/10 mg and 10/5 mg) (study B) each for 6 weeks. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity was assessed by urinary THF+5α-THF/THE.
Endocrine Centres within University Teaching Hospitals in the UK and Ireland.
Main outcome measures
Urinary corticosteroid metabolite profile and body composition assessment.
In study A, when patients were divided into three groups – patients not receiving HC and patients receiving HC≤20 mg/day or HC>20 mg/day – patients in the group receiving the highest daily dose of HC had significantly higher waist-to-hip ratio (WHR) than the ACTH replete group. They also had significantly elevated THF+5α-THF/THE (P=0.0002) and total cortisol metabolites (P=0.015). In study B, patients on the highest HC dose had significantly elevated total cortisol metabolites and all patients on HC had elevated THF+5α-THF/THE ratios when compared to controls.
In ACTH-deficient patients daily HC doses of >20 mg/day have increased WHR, THF+5α-THF/THE ratios and total cortisol metabolites. GC metabolism and induction of 11β-HSD1 may play a pivitol role in the development of the metabolically adverse hypopituitary phenotype.
Conor P Woods, Nicola Argese, Matthew Chapman, Christopher Boot, Rachel Webster, Vijay Dabhi, Ashley B Grossman, Andrew A Toogood, Wiebke Arlt, Paul M Stewart, Rachel K Crowley and Jeremy W Tomlinson
Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost.
We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.
In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary.
Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.